The correlation between platelet count and bleeding has been well described, although no formal methods for applying this information to clinical decisions are available. The authors developed a clinical prediction rule to guide the prophylactic use of platelet transfusions among patients with lymphoma or solid tumors. The Bleeding Risk Index (BRI) was developed from logistic regression analysis of a randomly selected 750-chemotherapy cycle derivation set using data from Day 1 of cycles. The sensitivity and specificity of a BRI-based prophylaxis strategy were compared in a 512-cycle validation set with two strategies based on initiation of prophylaxis when platelet counts fell below thresholds of 20,000 per microL or 10,000 per microL. Factors that were predictive of bleeding included any prior episode of bleeding (odds ratio [OR], 5.6; 95% confidence interval [95% CI], 2.2-14.0), treatment with a drug affecting platelet function (OR, 5.1; 95% CI, 2.0-12.6), bone marrow metastases (OR, 4.3; 95% CI, 1.7-10.8), a baseline platelet count < 75,000 per microL (OR, 3.5; 95% CI, 1.4-8.9), genitourinary or gynecologic malignancy (OR, 3.3; 95% CI, 1.3-8.2), a Zubrod performance status score > 2 (OR, 3.4; 95% CI, 1.4-8.5), and treatment with agents that were highly toxic to the bone marrow (OR, 2.2; 95% CI, 1.0-5.4). Compared with 20,000 and 10,000 platelet threshold strategies, the BRI-based strategy provided the best trade-off between sensitivity for major bleeding episodes (80%) and specificity for any bleeding (84%). Patients with lymphoma or solid tumors who are at high risk of bleeding can be identified reliably on Day 1 of a chemotherapy cycle. An individualized, BRI-based approach to bleeding prophylaxis provides a highly sensitive and specific alternative to traditional, nonindividualized platelet threshold strategies.